The identification of the genes and pathways that regulate the life span in simple model organisms has been invaluable to the initial understanding of the mechanisms of aging in mammals. The systems biology and genetic studies proposed in this application will help define the role of various signal transduction genes and pathways in the regulation of aging and resistance to the damage caused by various stresses in the unicellular eukaryote S. cerevisiae. These pathways are centered around the Ras and Sch9 proteins, which are conserved from yeast to humans, and are implicated in cancer and other diseases. The proposed studies will: 1) shed light on the fundamental molecular mechanisms responsible for the effects of previously identified pro-aging genes including RAS2 and SCH9, 2) investigate novel molecules, genes, and pathways that affect aging and resistance to damage and that may be conserved from yeast to humans, 3) develop a novel paradigm to study aging, that is simpler and more directly relevant to aging in mammals, 4) investigate the anti-aging molecular mechanisms of calorie restriction which appear to be conserved from yeast to mammals. The proposed studies will contribute to the description of the fundamental mechanisms of aging and also to the identification of novel genes and pathways that can protect against human diseases. Public Health Relevance: Historically, simple model systems including baker's yeast, nematodes, and flies have yielded a remarkable number of discoveries that have provided the foundation for the understanding and treatment of human diseases. The studies proposed in this application are aimed at understanding how yeast genes that are analogous to the human genes Ras and Akt affect aging and the protection of cells against damage. The understanding of how these genes regulate aging in yeast and other simple systems will accelerate the identification of genes and pathways that can be modulated to protect against diseases in humans (Longo and Finch, 2003). For example, mutations that cause activation of Akt or Ras accelerate aging in yeast but are also found in a major portion of human cancers.